Safety and pharmacokinetics of novel selective vascular endothelial growth factor receptor-2 inhibitor YN968D1 in patients with advanced malignancies

Department of Medical Oncology, Fudan University Shanghai Cancer Center, PR China.
BMC Cancer (Impact Factor: 3.36). 10/2010; 10(1):529. DOI: 10.1186/1471-2407-10-529
Source: PubMed


YN968D1 (Apatinib) selectively inhibits phosphorylation of VEGFR-2 and tumor angiogenesis in mice model. The study was conducted to determine the maximum tolerated dose (MTD), safety profile, pharmacokinetic variables, and antitumor activity in advanced solid malignancies.
This dose-escalation study was conducted according to the Chinese State Food and Drug Administration (SFDA) recommendations in patients with advanced solid tumors to determine the MTD for orally administered apatinib. Doses of continuously administered apatinib were escalated from 250 mg. Treatment continued after dose-escalation phase until withdrawal of consent, intolerable toxicities, disease progression or death.
Forty-six patients were enrolled. Hypertension and hand-foot syndrome were the two dose-limiting toxicities noted at dose level of 1000 mg. MTD was determined to be 850 mg once daily. Pharmacokinetic analysis showed early absorption with a half-life of 9 hours. The mean half-life was constant over all dose groups. Steady-state conditions analysis suggested no accumulation during 56 days of once-daily administration. The most frequently observed drug-related adverse events were hypertension (69.5%, 29 grade 1-2 and 3 grade 3-4), proteinuria (47.8%, 16 grade 1-2 and 6 grade 3-4), and hand-foot syndrome (45.6%, 15 grade 1-2 and 6 grade 3-4). Among the thirty-seven evaluable patients, PR was noted in seven patients (18.9%), SD 24 (64.9%), with a disease control rate of 83.8% at 8 weeks.
The recommended dose of 750 mg once daily was well tolerated. Encouraging antitumor activity across a broad range of malignancies warrants further evaluation in selected populations. unique identifier: NCT00633490.

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Available from: Ke Yu, Jul 15, 2015
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    • "Apatinib, also known as YN968D1, is a tyrosine kinase inhibitor that selectively inhibits the vascular endothelial growth factor receptor-2 (VEGFR2, also known as KDR). It is an orally bioavailable, small molecule agent which is thought to inhibit angiogenesis in cancer cells; specifically apatinib inhibits VEGF-mediated endothelial cell migration and proliferation, thus blocking new blood vessel formation in tumor tissue [6]. "
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    • "The increased understanding of the role of signaling pathways in promoting tumor angiogenesis has led to the rational development of new targeted therapeutic agents. Since aberrantly activated vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) signaling pathways are associated with enhanced angiogenesis in tumors [3] [4], inhibition of VEGFR and PDGFR signalings has been proposed as an effective therapeutic approach to solid malignancies. For example, sunitinib, a small molecular synthetic drug targeting multiple tyrosine kinase receptors, was the first ever oncology product approved by USA Food and Drug Administration for two indications, renal cell carcinoma and gastrointestinal stromal tumor, simultaneously [5]. "
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    • "The results from a phase 1 clinical study conducted in patients with advanced solid tumors have shown that apatinib can be well tolerated and exhibits substantial antitumor activity across a broad range of malignancies at the recommended dose of 750 mg once daily (Li et al., 2010). The pharmacokinetic parameters of apatinib in plasma were also calculated using noncompartmental analysis. "
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